WO2011143444A2 - Inducteurs, à base de diphénylbutylpipéridine, de l'autophagie - Google Patents

Inducteurs, à base de diphénylbutylpipéridine, de l'autophagie Download PDF

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WO2011143444A2
WO2011143444A2 PCT/US2011/036272 US2011036272W WO2011143444A2 WO 2011143444 A2 WO2011143444 A2 WO 2011143444A2 US 2011036272 W US2011036272 W US 2011036272W WO 2011143444 A2 WO2011143444 A2 WO 2011143444A2
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compound
autophagy
certain embodiments
compounds
disease
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WO2011143444A3 (fr
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Junying Yuan
Chengye Yuan
Gang Chen
Hong-Guang Xia
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Shanghai Institute of Organic Chemistry of CAS
Harvard University
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Shanghai Institute of Organic Chemistry of CAS
Harvard University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Autophagy is a lysosome-dependent process whereby proteins or damaged organelles within a cell are degraded (Klionsky, DJ., and Emr, S. D. (2000). Science. 290: 1717-21). During this process, an autophagosome having a double membrane encloses the component of the cell to be degraded, the autophagosome then fuses with a lysosome which carries out the function of degradation, which results in the recycling of amino acids. This system of degradation and recycling has been conserved to a high degree by evolution and is of key importance in development, growth, aging, illness, death, and other biological processes.
  • autophagy- lysosome pathway and the ubiquitin-proteasome pathway form the two principal degradation systems of eukaryotic cells; however, the two pathways have different functions in the cell.
  • Autophagy is primarily involved in the degradation of long-lived proteins, protein aggregates, and cellular organelles and other cellular components.
  • autophagy appears to have great significance for the treatment of various diseases caused by misfolded protein aggregates in specific tissues and cells.
  • autophagy is maintained at a very low basal level within a cell, but when confronted with starvation or other stress conditions, the level of autophagy is rapidly up-regulated.
  • ATG autophagy-related genes
  • the proteins encoded by these seventeen genes can be divided into four types, comprising several kinds of serine- threonine kinase (Atgl, Atgl3, Atgl7) that are involved in regulating upstream autophagy signals (such as mTOR); proteins that are involved in regulating lipase/kinase signal compounds during the initiation stage of the autophagy process (Atg6, Atgl4, Vps34, and Vpsl5); two types of new ubiquitin-like conjugation systems (the Atg8 and Atgl2 systems) that are involved in autophagosome formation; and proteins (Atg2, Atg9, and Atgl8) that assist ATG molecules bound to an autophagosome during the autophagosome formation process to dissociate from the mature autophagosome.
  • Atgl serine- threonine kinase
  • Atgl3, Atgl7 proteins that are involved in regulating upstream autophagy signals (such as mTOR)
  • Autophagy can be induced by many factors both from within and outside the cell, including starvation, nutrient deprivation, bacterial infection, damage to cellular organelles, and protein mismatching. At present, only the mechanism underlying starvation-induced autophagy is understood with relative clarity. However, at the same time, it has been demonstrated that a number of intracellular signaling molecules, such as AMPK, mTOR, C3PI3K, and MAPK, are also involved in autophagy regulation.
  • Autophagy has been proposed to play complex roles in development and treatment of cancers. Activation of autophagy may promote tumor cell survival under metabolic stress and function as a tumor suppression mechanism by preventing necrotic cell death and subsequent inflammation which favors tumor growth (White, E. (2008). Autophagic cell death unraveled: Pharmacological inhibition of apoptosis and autophagy enables necrosis. Autophagy 4, 399-401).
  • Beclin 1 an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100, 15077-15082) and decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer (Shen, Y., Li, D.D., Wang, L.L., Deng, R., and Zhu, X.F. (2008). Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy 4, 1067-8). Thus, chronic suppression of autophagy may stimulate tumorigenesis.
  • imatinib-resistant cell lines BaF3/T315I and BaF3/E255K
  • inhibition of autophagy sensitizes tumor cells to imatinib-induced cell death.
  • the block of autophagy has been proposed to be a new strategy for the treatment of CML (Mishima, Y., Terui, Y., Taniyama, A., Kuniyoshi, R., Takizawa, T., Kimura, S., Ozawa, K., and Hatake, K. (2008).
  • Autophagy and autophagic cell death are next targets for elimination of the resistance to tyrosine kinase inhibitors.
  • a conditional knockout mouse that lacks the autophagy-related (Atg) gene Atg5 in the pancreatic acinar cells has shown significantly reduced severity of acute pancreatitis induced by cerulein (Ohmuraya, M., and Yamamura, K. (2008).
  • Autophagy and acute pancreatitis a novel autophagy theory for trypsinogen activation.
  • Autophagy 4 1060- 1062 Thus autophagy exerts a detrimental effect in pancreatic acinar cells by activation of trypsinogen to trypsin.
  • Inhibitors of autophagy may provide important new therapeutics for acute pancreatitis.
  • One aspect of the present invention relates to an autophagy inducing compound represented by compounds of formula I:
  • R is aryl or heteroaryl
  • R 2 is aryl or heteroaryl
  • R 3 is fluorenyl or fluorenyl-like
  • R 4 is aryl, heteroaryl
  • W, Y and Z are independently for each occurrence selected from the group
  • E is arylene or heteroarylene
  • R 5 is hydroxy, alkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, heteroaralkylcarbonyloxy, cyano, amino or amido;
  • R 6 is hydrogen or alkyl
  • R 7 is aryl or heteroaryl
  • R 8 is hydrogen or alkyl.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an autophagy inducing compound in an amount effective for treating an autophagy associated disease, wherein the compound is selected from at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically- protected form, enantiomer or stereoisomer thereof.
  • the compound is selected from at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically- protected form, enantiomer or stereoisomer thereof.
  • composition further comprises a pharmaceutically acceptable carrier.
  • the autophagy associated disease is a disease caused by misfolded protein aggregates.
  • the disease caused by misfolded protein aggregates is selected from the group consiting of: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia, oculopharyngeal muscular dystrophy, prion diseases, fatal familial insomnia, alpha- 1 antitrypsin deficiency, dentatorubral pallidoluysian atrophy, frontal temporal dementia, progressive supranuclear palsy, x-linked spinobulbar muscular atrophy, and neuronal intranuclear hyaline inclusion disease.
  • the disease associated with misfolded protein aggregates is a chronic disease.
  • the autophagy associated disease is cancer.
  • Another aspect of the present invention relates to a method of inducing autophagy in a cell, the method comprising contacting the cell with an autophagy inducing compound in an amount effective to induce autophagy in the cell.
  • the autophagy inducing compound is selected from at least one compound of formula I, or a
  • the cell is present in a subject. In certain embodiments, the cell is present in an in vitro cell culture. In certain
  • the cell is contacted with an autophagy inducing compound at a
  • the cell is contacted with an autophagy inducing compound at a concentration of about 3.0 ⁇ to about 9.0 ⁇ .
  • the cell is selected from the group consisting of neural cells, glial cells, such as astrocytes, oligodendrocytes, ependymal cells, Schwann cells, lymphatic cells, epithelial cells, endothelial cells, lymphocytes, cancer cells, and haematopoietic cells.
  • Another aspect of the invention relates to a method of treating an autophagy associated disease in a subject; the method includes administering to the subject an autophagy inducing compound in an amount effective to treat the disease, or a composition comprising the compound, thereby treating the disease in the subject.
  • the autophagy associate disease is a disease caused by misfolded protein aggregates.
  • the disease caused by misfolded protein aggregates is selected from the group including: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia, oculopharyngeal muscular dystrophy, prion diseases, fatal familial insomnia, alpha- 1 antitrypsin deficiency, dentatorubral pallidoluysian atrophy, frontal temporal dementia, progressive supranuclear palsy, x-linked spinobulbar muscular atrophy, and neuronal intranuclear hyaline inclusion disease.
  • the disease associated with misfolded protein aggregates is a chronic disease.
  • the autophagy associated disease is cancer.
  • the autophagy inducing compound is selected from at least one compound of formula I and pharmaceutically acceptable salts thereof.
  • the autophagy inducing compound is administered at a concentration of about 0.1 ⁇ to about 15.0 ⁇ .
  • the autophagy inducing compound is administered at a concentration of about 3.0 ⁇ to about 9.0 ⁇ .
  • Another aspect of the invention relates to a kit which includes: (i) a pharmaceutical composition comprising an autophagy inducing compound and (ii) instructions for administering the composition to a subject for the treatment of an autophagy associated disease.
  • the autophagy inducing compound is selected from at least one compound of formula I and pharmaceutically acceptable salts thereof.
  • Figure 1 depicts DPBPs autophagy regulators: Fluspirilene (1), Pimozide (2), Trifluoperazine (3) and Penfluridol (4).
  • Figure 2 depicts a synthetic route to compounds 36-41 and 45-54.
  • Reagents and conditions (a) THF, Reflux; (b) EtOH, Con. HC1, Reflux; (c) CBr 4 , Ph 3 P, CH 2 C1 2 , 0 °C- RT; (d) Pd/C, H 2 , EtOH, RT; and (e) piperidines, NaC0 3 , KI, CH 3 CN, Reflux.
  • Figure 3 depicts a synthetic route to compounds 42-44 and 55-57.
  • Reagents and conditions (a) Et 2 0, Reflux; (b) MgBr 2 , Et 2 0, Reflux; (c) Pd/C, H 2 , EtOH, RT; and (d) piperidines, NaC0 3 , KI, CH 3 CN, Reflux.
  • Figure 4 depicts a synthetic route to compounds 67-76. Reagents and conditions: (a) THF, Reflux; (b) EtOAc, 3M HC1 RT; and (c) diphenylbutyl bromide, NaC0 3 , KI, CH 3 CN, Reflux.
  • Figure 5 depicts a synthetic route to compounds 77-90. Reagents and conditions:
  • Figures 6 to 11 depicts tables of EC50 values for selected autophagy inducers.
  • Figure 12 depicts DPBP autophagy regulators: Pimozide (2), and DPBPs scaffolds, wherein the piperidines have 6,5-fused rings, P-1-56 and P-2-56, or 6,6-fused rings, P-1-66 and P-2-66 at their 4-position (wherein W, X, Y and Z are as defined herein).
  • Figures 13 and 14 depict tables of EC50 values for selected autophagy inducers
  • Figures 15 and 16 depict a synthetic route to compounds 142-150, 152, 153, 156- 58, 160 and 161.
  • Reagents and conditions (a) NaH, DMF, 90 °C; (b) TFA, CH 2 C1 2 , 0 °C- RT; (c) NaBH(OAc) 3 , DCE, RT; (d) (Cl 3 CO) 3 CO, py., THF; (e) KOH, MeOH, Reflux; (f) Pd/C, H 2 , EtOH, RT; (g) NaBH 3 CN, AcOH; and (h) N-Boc piperidone, NaBH(OAc) 3 , DCE, RT.
  • Figure 17 depicts a synthetic route to compounds 163-180.
  • Reagents and conditions (a) PPA, 180 °C; (b) BH 3 .THF; (c) N-Boc piperidone, NaBH(OAc) 3 , DCE, RT; (d)TFA, CH 2 C1 2 , 0 °C-RT; (e) DMF, 90 °C; and (f) DEAD, Ph 3 P, THF.
  • Figures 18 and 19 depict tables of EC 50 values for selected P-l-56 autophagy inducers.
  • Figure 20 depicts a table of EC50 values for selected P-2-56 autophagy inducers.
  • Figures 21 and 22 depict a synthetic route to compounds 218-223.
  • Reagents and conditions (a) NaBH 3 CN, BF 3 .Et 2 0; (b) N-Boc piperidone, NaBH(OAc) 3 , DCE, RT; (c) TFA, CH 2 CI 2 , 0 °C-RT; (d) TsOH, toluene; (e) L1AIH 4 , dioxane; (f) CDI, CH 3 CN, Reflux; (g) Pd(OH) 2 /H 2 , MeOH; (h) sulfamide, pyridine, Reflux; (i) HCOOH, Reflux; (j) NaN0 2 , coned HC1; and (k) CS 2 ,EtOH, Reflux.
  • Figures 23 and 24 depict a synthetic route to compounds 224-233.
  • Reagents and conditions (a) NaBH 4 , NiCl 2 , MeOH; (b) N-Boc piperidone, NaBH(OAc) 3 , DCE, RT; (c) TFA, CH 2 CI 2 , 0 °C-RT; (d) NaBH 4 , MeOH; (e) CDI, CH3CN, Reflux; (f) Pd(OH) 2 /H 2 , MeOH; (h) NaN0 2 , coned HC1; (i) CH(OMe) 3 .
  • Figure 25 depicts a table of EC50 values for selected P-l-66 autophagy inducers.
  • Figures 26 and 27 depict tables of EC50 values for selected P-2-66 autophagy inducers.
  • Figure 28 depicts a table of EC 50 values for selected autophagy inducers.
  • Figure 29 depicts compounds 238 and 239 and their autophagy EC50 values.
  • the invention relates to autophagy inducing compounds that are useful in treating or preventing autophagy associated diseases, e.g., diseases caused by misfolded protein aggregates.
  • autophagy associated diseases e.g., diseases caused by misfolded protein aggregates.
  • One aspect of the invention relates to
  • diphenylbutylpiperidines which have autophagy inducing activity.
  • Another aspect of the invention relates to an effective synthetic route to a diphenylbutyl bromide intermediate useful in the preparation of compounds of the invention.
  • Another aspect of the invention relates to novel diphenylbutylpiperidines which have improved autophagy inducing activity when comapared to known diphenybutylpiperidines. For example, modification of compounds 1 and 4 resulted in up to about a 10-fold increase in autophagy inducing activity (e.g., compound 48).
  • Another aspect of the invention relates to compounds derived from compound 2, in which different 5,6- and 6,6-ring systems are substituted at the 4-position of piperidine ring, as shown in Figure 12 (Klionsky, D.J.; Emr, S.D. Science. 2000, 290, 1717; and Levine B, Yuan J. J Clin Invest. 2005, 115, 2679).
  • an element means one element or more than one element.
  • a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • autophagy refers to the catabolic process involving the degradation of a cell's own components; such as, long lived proteins, protein aggregates, cellular organelles, cell membranes, organelle membranes, and other cellular components.
  • the mechanism of autophagy may include: (i) the formation of a membrane around a targeted region of the cell, separating the contents from the rest of the cytoplasm, (ii) the fusion of the resultant vesicle with a lysosome and the subsequent degradation of the vesicle contents.
  • autophagy may refer to one of the mechanisms by which a starving cell re-allocates nutrients from unnecessary processes to more essential processes.
  • autophagy may inhibit the progression of some diseases and play a protective role against infection by intracellular pathogens.
  • the term "compound” is intended to mean a substance made up of molecules that further consist of atoms.
  • a compound generally refers to a chemical entity, whether in the solid, liquid or gaseous phase, and whether in a crude mixture or purified and isolated.
  • Compounds encompass the chemical compound itself as well as, where applicable: amorphous and crystalline forms of the compound, including polymorphic forms, said forms in mixture or in isolation; free acid and free base forms of the compound; isomers of the compound, including geometric isomers, optical isomers, and tautomeric isomers, said optical isomers to include enantiomers and diastereomers, chiral isomers and non-chiral isomers, said optical isomers to include isolated optical isomers or mixtures of optical isomers including racemic and non- racemic mixtures; said geometric isomers to include transoid and cisoid forms, where an isomer may be in isolated form or in admixture with one or more other isomers; isotopes of the compound, including deuterium- and tritium-containing compounds, and including compounds containing radioisotopes, including therapeutically- and diagnostically-effective radioisotopes; multimeric forms of the compound, including dimeric, trimeric, etc.
  • salts of the compound including acid addition salts and base addition salts, including organic counterions and inorganic counterions, and including zwitterionic forms, where if a compound is associated with two or more counterions, the two or more counterions may be the same or different; and solvates of the compound, including hemisolvates, monosolvates, disolvates, etc., including organic solvates and inorganic solvates, said inorganic solvates including hydrates; where if a compound is associated with two or more solvent molecules, the two or more solvent molecules may be the same or different
  • autophagy inducing compound refers to a compound that induces autophagy in a cell.
  • autophagy inducing compound comprises the specific compounds disclosed herein.
  • misfolded protein aggregates refers to a mass of misfolded proteins, wherein said proteins have not adopted the appropriate three-dimensional structure, i.e., tertiary structure.
  • the misfolded proteins may have clustered together to form an assemblage of misfolded proteins.
  • autophagy associated disease includes a disease that can be treated by the induction of autophagy.
  • diseases include diseases caused by misfolded protein aggregates.
  • disease caused by misfolded protein aggregates is intended to include any disease, disorder or condition associated with or caused by misfolded protein aggregates.
  • such diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia, oculopharyngeal muscular dystrophy, prion diseases, fatal familial insomnia, alpha- 1 antitrypsin deficiency, dentatorubral pallidoluysian atrophy, frontal temporal dementia, progressive supranuclear palsy, x-linked spinobulbar muscular atrophy, and neuronal intranuclear hyaline inclusion disease.
  • autophagy associated disease also includes cancer e.g., any cancer wherein the induction of autophagy would inhibit cell growth and division, reduce mutagenesis, remove mitochondria and other organelles damaged by reactive oxygen species or kill developing tumor cells. Autophagy associated diseases can be chronic diseases.
  • chronic disease refers to a persistent and lasting disease or medical condition, or one that has developed slowly.
  • an autophagy inducing compound of the present invention refers to the amount of an autophagy inducing compound of the present invention required to treat or prevent an autophagy associated disease, e.g., a disease associated with misfolded protein aggregates.
  • the effective amount of an autophagy inducing compound of the invention used to practice the invention for therapeutic or prophylactic treatment of autophagy associated diseases varies depending upon the manner of administration, the age, body weight, and general health of the subject.
  • An effective amount of an autophagy inducing compound, as defined herein may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the autophagy inducing compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • an effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the autophagy inducing compound are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount of an autophagy inducing compound may range from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • treatment of a subject with a therapeutically effective amount of an autophagy inducing compound can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with an autophagy inducing compound in the range of between about 0.1 to 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks.
  • the effective dosage of an autophagy inducing compound used for treatment may increase or decrease over the course of a particular treatment.
  • composition refers to a composition containing an autophagy inducing compound of the invention formulated with one or more
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or any other formulation described herein.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • pharmaceutically acceptable carrier refers to any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like, that may be used as a media for a pharmaceutically acceptable substance.
  • the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, or have another action.
  • the autophagy inducing compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
  • treating refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • To “prevent disease” refers to prophylactic treatment of a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease.
  • To “treat disease” or use for “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease to improve or stabilize the subject's condition.
  • treating is the administration to a subject either for therapeutic or prophylactic purposes.
  • subject includes humans, and non-human animals amenable to therapy, e.g., preferably mammals and animals susceptible to an autophagy associated disease, such as a disease associated with misfolded protein aggregates, including non- human primates, transgenic animals, mice, rats, dogs, cats, rabbits, pigs, chickens, sheep, horses, and cows.
  • an autophagy associated disease such as a disease associated with misfolded protein aggregates, including non- human primates, transgenic animals, mice, rats, dogs, cats, rabbits, pigs, chickens, sheep, horses, and cows.
  • the subject is a human subject
  • each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein below.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the term "lower” when appended to any of the groups listed below indicates that the group contains less than seven carbons (i.e. six carbons or less).
  • “lower alkyl” refers to an alkyl group containing 1-6 carbons
  • lower alkenyl refers to an alkyenyl group containing 2-6 carbons.
  • saturated refers to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
  • unsaturated as used herein, pertains to compounds and/or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond.
  • aliphatic refers to compounds and/or groups which are linear or branched, but not cyclic (also known as “acyclic” or “open-chain” groups).
  • cyclic refers to compounds and/or groups which have one ring, or two or more rings (e.g., spiro, fused, bridged).
  • aromatic refers to a planar or polycyclic structure characterized by a cyclically conjugated molecular moiety containing 4n+2 electrons, wherein n is the absolute value of an integer.
  • Aromatic molecules containing fused, or joined, rings also are referred to as bicylic aromatic rings.
  • bicyclic aromatic rings containing heteroatoms in a hydrocarbon ring structure are referred to as bicyclic heteroaryl rings.
  • hydrocarbon refers to an organic compound consisting entirely of hydrogen and carbon.
  • heteroatom refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl means an aliphatic or cyclic hydrocarbon radical containing from 1 to 12 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-methylcyclopentyl, and 1-cyclohexylethyl.
  • alkylene is art-recognized, and as used herein pertains to a bidentate moiety obtained by removing two hydrogen atoms of an alkyl group, as defined above.
  • alkenyl as used herein means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkynyl as used herein means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • Carbocyclyl as used herein means monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g. phenyl).
  • carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1- cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.
  • heterocyclyl include non-aromatic, ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heterocyclic rings azepines, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.
  • heterocyclyl groups of the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl,
  • alkylene moiety e.g. methylene
  • aryl as used herein means a phenyl group, naphthyl or anthracenyl group.
  • the aryl groups of the present invention can be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkyn
  • haloalkylcarbonyl fluoroalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynylsul
  • arylalkyl or "aralkyl” as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of aralkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, and 2-naphth-2-ylethyl.
  • fluorenyl refers to a radical having the chemical formula and numbering scheme indicated below:
  • 9 indicates the bridgehead carbon atom.
  • the remaining carbon atoms available to accept substituents are indicated by numbers 1-4 on one phenyl group of the ligand, and numbers 5-8 on the other phenyl group of the fluorenyl group.
  • the fluorenyl groups of the invention are substituted with 0, 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl,
  • fluroralkylsulfonyl alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony, aminosulfonyl, sulfuric acid, alkylsulfmyl, haloalkylsulfmyl, fluroralkylsulfinyl, alkenylsulfmyl, alkynylsulfinyl, alkoxysulfmyl, haloalkoxysulfmyl, fluroralkoxysulfmyl, alkenyloxysulfmyl,
  • alkynyloxysulfiny aminosulfmyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
  • fluoroalkylcarbonyl alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, hal
  • fluorenyl-like refers to a fluorenyl radical, as described above, wherein 0, 1, 2, 3 or 4 of the carbons, excluding the C-9 carbon, is/are replaced with a nitrogen; and/or the bond between the C-4' and C-5' carbons is replaced with -S-, -0-, - N(H)-, -CH 2 - or -CH 2 CH 2 -.
  • the fluorenyl-like groups of the invention are substituted, on the aromatic rings or on the atoms between C-4' and C-5', with 0, 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl
  • alkynyloxysulfiny aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
  • fluoroalkylcarbonyl alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, hal
  • alkylene moiety e.g. methylene
  • heteroaryl as used herein include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heteroatom such as nitrogen, oxygen, or sulfur.
  • heteroaryl groups of the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralk
  • alkynyloxysulfony aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyl
  • heteroarylene is art-recognized, and as used herein pertains to a bidentate moiety obtained by removing two hydrogen atoms from adjacent atoms of a heteroaryl ring, as defined above.
  • heteroarylalkyl or “heteroaralkyl” as used herein means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heteroarylalkyl include, but are not limited to, pyridin- 3-ylmethyl and 2-(thien-2-yl)ethyl.
  • halo or halogen means -CI, -Br, -I or -F.
  • haloalkyl means an alkyl group, as defined herein, wherein at least one hydrogen is replaced with a halogen, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • fluoroalkyl means an alkyl group, as defined herein, wherein all the hydrogens are replaced with fluorines.
  • hydroxy as used herein means an -OH group.
  • alkoxy as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkyenyloxy “alkynyloxy”, “carbocycyloxy”, and “heterocycyloxy” are likewise defined.
  • haloalkoxy as used herein means an alkoxy group, as defined herein, wherein at least one hydrogen is replaced with a halogen, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • fluoroalkyloxy is likewise defined.
  • aryloxy as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • heteroaryloxy as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • heteroaryloxy is likewise defined.
  • arylalkoxy or "arylalkyloxy” as used herein means an arylalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • heteroarylalkoxy is likewise defined. Representative examples of aryloxy and heteroarylalkoxy include, but are not limited to, 2-chlorophenylmethoxy, 3-trifluoromethyl- phenylethoxy, and 2,3-dimethylpyridinylmethoxy.
  • sulfhydryl or "thio" as used herein means a -SH group.
  • alkylthio as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur.
  • Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • haloalkylthio fluoroalkylthio
  • alkyenylthio alkynylthio
  • arylthio as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an sulfur.
  • heteroarylthio is likewise defined.
  • arylalkylthio or “aralkylthio” as used herein means an arylalkyl group, as defined herein, appended to the parent molecular moiety through an sulfur.
  • heteroarylalkylthio is likewise defined.
  • alkylsulfonyl as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • haloalkylsulfonyl include fluroralkylsulfonyl, “alkenylsulfonyl”, “alkynylsulfonyl”, “carbocycylsulfonyl”, “heterocycylsulfonyl", “arylsulfonyl”,
  • aralkylsulfonyl "heteroarylsulfonyl” and “heteroaralkylsulfonyl” are likewise defined.
  • alkoxysulfonyl as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • alkoxysulfonyl include, but are not limited to,
  • aralkyloxysulfonyl "hetero aryloxy sulfonyl” and “heteroaralkyloxysulfonyl” are likewise defined.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and
  • nonafluorobutanesulfonyl groups respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • aminosulfonyl as used herein means an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group.
  • oxy refers to a -O- group.
  • alkylcarbonyl as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1- oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • haloalkylcarbonyl "fluoroalkylcarbonyl”, “alkenylcarbonyl”, “alkynylcarbonyl”, “carbocycylcarbonyl”, “heterocycylcarbonyl”, “arylcarbonyl”, “aralkylcarbonyl”, “heteroarylcarbonyl”, and “heteroaralkylcarbonyl” are likewise defined.
  • alkoxycarbonyl as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxy carbonyl.
  • heteroaryoaralkyloxycarbonyl are likewise defined.
  • alkylcarbonyloxy as used herein means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • haloalkylcarbonyloxy fluoroalkylcarbonyloxy
  • alkenylcarbonyloxy alkynylcarbonyloxy
  • aralkylcarbonyloxy "heteroarylcarbonyloxy”, and “heteroaralkylcarbonyloxy” are likewise defined.
  • alkylsulfonyloxy as used herein means an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • haloalkylsulfonyloxy fluroralkylsulfonyloxy
  • alkenylsulfonyloxy alkylsulfonyloxy
  • alkynylsulfonyloxy "carbocycylsulfonyloxy”
  • heterocycylsulfonyloxy
  • heteroaryloxysulfonyloxy and “heteroaralkyloxysulfonyloxy”
  • amino refers to -NH 2 and substituted derivatives thereof wherein one or both of the hydrogens are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocycyl, heterocycyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocycylcarbonyl,
  • heterocycylcarbonyl arylcarbonyl, aralkylcarbonyl, heteroarylcarnbonyl,
  • Representative examples include, but are not limited to methylamino, acetylamino, and dimethylamino.
  • amino as used herein means an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl.
  • cyano as used herein means a -C ⁇ N group.
  • nitro as used herein means a -N0 2 group.
  • azido as used herein means a -N 3 group.
  • phosphinyl as used herein includes -PH 3 and substituted derivatives thereof wherein one, two or three of the hydrogens are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocycyl, heterocycyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, and amino.
  • sil as used herein includes H 3 Si- and substituted derivatives thereof wherein one, two or three of the hydrogens are independently replaced with subsitutuents selected from alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocycyl, heterocycyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • TMS trimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • TPS/TBDMS tert-butyldimethylsilyl
  • TIPS triisopropylsilyl
  • SEM [2-(trimethylsilyl)ethoxy]methyl
  • silyloxy as used herein means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and
  • One aspect of the invention relates to autophagy inducing compounds. Recently, a high-throughput image-based screen was used to identified seven FDA-approved drugs which can induce autophagy without inducing cell death (see International Patent
  • Fluspirilene an FDA-approved phenothiazine tranquilizer (antipsychotic drug), has been used to treat schizophrenia (Meijer, AJ. and Codogno, P. Int J Biochem Cell Biol. 2004, 36, 2445-62). This molecule may function by blocking adrenaline and dopamine transport in the central nervous system (Janssen, P.A., Niemegeers, CJ., Schellekens, K.H., et al. Arzneiffen 1974, 20, 1689-98).
  • Trifluoperazine is another FDA-approved tranquilizer, which, like fluspirilene, can effectively treat acute schizophrenia (Janssen, P. A., Niemegeers, CJ., Schellekens, K.H., et al. Arzneistoffforschung 1970, 20, 1689-98).
  • trifluoperazine has also been reported to inhibit calmodulin activity and mitochondrial permeability transition pore
  • MTP calcium ion channel blocker
  • Pimozide is an FDA-approved tranquilizer used in the treatment of chronic schizophrenia. It may act on central aminergic receptors. At high doses, this compound may also affect the degradation of norepinephrine.
  • niguldipine acts as an inhibitor of Type-T Ca 2+ current in cardiac myocytes.
  • nicardipine is frequently used to treat chronic angina pectoris, high blood pressure, and Raynaud's phenomenon.
  • Amiodarone is another highly effective anti- arrhythmia drug. It also blocks Ca 2+ channels.
  • Loperamide is a heterocyclic piperidine derivative. As an FDA-approved drug to treat diarrhea, it can effectively improve gastrointestinal symptoms. Loperamide can block high-voltage-activated Ca 2+ channels and reactions to N-methyl-D-aspartate in the hippocampal neurons of rabbits and mice (Girotti, F., Carella, F., Scigliano, G., et al. J Neurol Neurosurg Psychiatry 1984, 47: 848-52). In addition, loperamide can also block voltage-dependant Ca 2+ channels in cultured dorsal root ganglions (Church, J. Fletcher, EJ., Abdel-Hamid, K. et al. Mol Pharmacol. 1995, 45: 747-57).
  • Penitrem A a fungal neurotoxin discovered in ryegrass, can selectively block Ca 2+ - activated K + channels (100% blockage is achieved by 10-nM penitrem A). It has been reported that this compound may possess marked neurotoxicity and can cause severe tremors or ataxia (Hagiwara, K., Nakagawasai, O., Murata, A., et al. Neurosci Res. 2003, 46, 493-7); however the results presented in International Patent Application publication number WO/2009/049242 show that this drug does not destroy H4.
  • DPBPs were originally antagonists of the D 2 receptor and were clinically used to treat various forms of psychosis (Seeman, P.; Lee, T.; Chau-Wong, M; Wong. K. Nature.
  • R 1 is aryl or heteroaryl
  • R 2 is aryl or heteroaryl
  • R 3 is fluorenyl or fluorenyl-like
  • n 0, 1, 2 or 3;
  • W, Y and Z are independently for each occurrence selected from the rou
  • E is arylene or heteroarylene
  • R 5 is hydroxy, alkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, heteroaralkylcarbonyloxy, cyano, amino or amido;
  • R 6 is hydrogen or alkyl
  • R 7 is aryl or heteroaryl
  • R 8 is hydrogen or alkyl.
  • W, X, Y and Z certain selections of W, X, Y and Z, such as when W, X, Y and Z are all ⁇ 0 ⁇ , result in non-sensical compounds. In other words, the selection of W, X, Y and Z must be in accordance with permitted valence and result in a stable compound.
  • the invention relates to any of the aforementioned
  • A is not (i.e., provided that the compound is not 1, 2 or 4, as depicted in Figure 1).
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R
  • the invention rel ed compounds and attendant definitions, wherein R
  • the invention relates to any of the aforementioned compounds and attendant definitions, whereiinn R is or In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is aryl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is heteroaryl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is phenyl substituted with 0-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl,
  • fluroralkylsulfonyl alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony, aminosulfonyl, sulfuric acid, alkylsulfmyl, haloalkylsulfmyl, fluroralkylsulfinyl, alkenylsulfmyl, alkynylsulfinyl, alkoxysulfmyl, haloalkoxysulfinyl, fluroralkoxysulfinyl, alkenyloxysulfinyl,
  • alkynyloxysulfiny aminosulfmyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
  • fluoroalkylcarbonyl alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, hal
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is a 3-substituted phenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is a 4-substituted phenyl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is a 3-substituted phenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is a 3,4-disubstituted phenyl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is phenyl substituted 0-5 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy and haloalkoxy. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is phenyl substituted in the 3- or 4- position with halo, alkyl, haloalkyl, alkoxy or haloalkoxy. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 is 3-alkyl-4-halophenyl or 3-haloalkyl-4-halophenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions,
  • the invention relates to any of the aforementioned compounds and
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is aryl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is heteroaryl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is phenyl substituted with 0-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl
  • alkynyloxysulfiny aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
  • fluoroalkylcarbonyl alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, hal
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is a 3-substituted phenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is a 4-substituted phenyl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is a 3-substituted phenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is a 3,4-disubstituted phenyl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is phenyl substituted 0-5 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy and haloalkoxy. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is phenyl substituted in the 3- or 4- position with halo, alkyl, haloalkyl, alkoxy or haloalkoxy. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 2 is 3-alkyl-4-halophenyl or 3-haloalkyl-4-halophenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R is
  • the invention relates to any of the aforementioned compounds and
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 and R 2 are the same. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 1 and R 2 are not the same.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 3 is fluorenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 3 is fluorenyl-like.
  • the invention relates to any of the aforementioned
  • alkyl independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralkoxysulfonyl, alkenyloxysulfony
  • alkynyloxysulfony aminosulfonyl, sulfuric acid, alkylsulfmyl, haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl, alkynylsulfmyl, alkoxysulfinyl, haloalkoxysulfinyl, fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfmy, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloal
  • 0-8 substitutents independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy and haloalkoxy.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein n is 0. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein n is 1. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein n is 2. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein n is 3. In certain embodiments, the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is aryl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is heteroaryl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is phenyl substituted with 0-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl,
  • fluroralkylsulfonyl alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony, aminosulfonyl, sulfuric acid, alkylsulfmyl, haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, fluroralkoxysulfmyl, alkenyloxysulfinyl,
  • alkynyloxysulfiny aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
  • fluoroalkylcarbonyl alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, hal
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is a 3-substituted phenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is a 4-substituted phenyl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is a 3-substituted phenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is a 3,4-disubstituted phenyl.
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is phenyl substituted 0-5 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy and haloalkoxy. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is phenyl substituted in the 3- or 4- position with halo, alkyl, haloalkyl, alkoxy or haloalkoxy. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 4 is 3-alkyl-4-halophenyl or 3-haloalkyl-4-halophenyl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions,
  • the invention relates to any of the aforementioned compounds and
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 5 is hydroxy, alkyloxy, alkylcarbonyloxy, cyano or amino. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 5 is hydroxy, alkyloxy or alkylcarbonyloxy. In certain embodiments, the invention relates to any of the
  • the invention relates to any of the aforementioned
  • the invention relate of the aforementioned
  • the invention relate of the aforementioned
  • the invention rel e aforementioned
  • the invention rel e aforementioned
  • X is XX .
  • the invention relates to any of the
  • the invention relates to any of the aforementioned compounds and attendant In certain embodiments, the invention rel e aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions,
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is H . In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is H . In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is
  • the invention relates to any of the aforementioned
  • the invention rel e aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is ⁇ ff, * ⁇ ⁇ ' ⁇ j n cer tain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is . i n certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is . In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, where In certain embodiments, the invention relates to any of the aforementioned compounds and
  • the invention relate e aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to an of the aforementioned com ounds and attendant any
  • the invention relates to any of the aforementioned compounds and attendant definitions, In certain embodiments, the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is R R . In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is ⁇ XX ⁇ . In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relate of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is XX ⁇ . In certain embodiments, the invention relates to any of the
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is .
  • the invention relates to any of the aforementioned compounds and attendant
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is In certain embodiments of the aforementioned compounds and attendant definitions,
  • the invention rel e aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions,
  • the invention re to any of the aforementioned compounds and attendant definitions, wherein Z is .
  • the invention relates to any of the aforementioned compounds and attendant
  • the invention relates to any of the aforementioned compounds and attendant definitions, where In certain embodiments, the invention relates to any of the aforementioned compounds and
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein W is In certain embodiments, the invention relate of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relate of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Y is ⁇ .
  • the invention relat e aforementioned
  • the invention relates to any of the
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is .
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is ⁇ j n cer ain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein Z is * N In certain embodiments, of the aforementioned compounds and
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein W is R 8 . In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein W is In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein W is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein E is arylene. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein E is heteroarylene. In certain embodiments, the invention relates to any of the
  • E is ed with 0-4 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroral
  • haloalkylcarbonyl fluoroalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynylsul
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein E is
  • the invention relate of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • R 4 is In certain embodiments, the invention relates to an of the aforementioned
  • R 4 is In certain embodiments, the invention relates to any of the
  • the invention relate of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R is .
  • R is .
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relate of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relate of the aforementioned
  • the invention relate of the aforementioned
  • the invention relate of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 8 is hydrogen.
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 6 is hydrogen. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 6 is alkyl. In certain embodiments, the invention relates to any of the
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 7 is aryl. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein heteroaryl. In certain embodiments, the invention relates to any of the
  • R 7 is phenyl substituted with 0-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl
  • alkynyloxysulfiny aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
  • fluoroalkylcarbonyl alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, hal
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 7 is phenyl.
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 6 is hydrogen. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein R 6 is alkyl. In certain embodiments, the invention relates to any of the
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein E is arylene. In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein E is heteroarylene. In certain embodiments, the invention relates to any of the
  • E is ed with 0-4 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocycyloxy, heterocycyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroral
  • haloalkylcarbonyl fluoroalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynylsul
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein E is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is In certain embodiments, the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • the invention relates to any of the aforementioned compounds and attendant definitions, wherein the compound is
  • pharmaceutically compatible counterions i.e., pharmaceutically acceptable salts.
  • a "pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a compound of this invention.
  • a “pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para- bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,
  • Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N- (hydroxy lower alkyl)-amines, such as N,
  • Certain compounds of the invention and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of the invention and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of the invention may contain one or more chiral centers, and exist in different optically active forms.
  • compounds of the invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by
  • a compound of the invention When a compound of the invention contains more than one chiral center, it may exist in diastereoisomeric forms.
  • the diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of the invention and mixtures thereof.
  • Certain compounds of the invention may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of the invention and mixtures thereof.
  • Certain compounds of the invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of compounds of the invention and mixtures thereof.
  • Certain compounds of the invention may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of the invention and mixtures thereof.
  • the present invention also includes pro-drugs.
  • pro-drug refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • pro-drug a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydro lyzed to the carboxylic acid once inside the cell where water solubility is beneficial.
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -C(0) 2 H or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C 4 )alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, (C 4 -Cc))l-(alkanoyloxy)ethyl, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)amino
  • exemplary pro-drugs release an alcohol or amine of a compound of the invention wherein the free hydrogen of a hydroxyl or amine substituent is replaced by (C i -C 6 )alkanoyloxymethyl, 1 -((C i -C 6 )alkanoyloxy)ethyl, 1 -methyl- 1 -((C i - C 6 )alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyl-oxymethyl, N-(Ci-C 6 )alkoxycarbonylamino- methyl, succinoyl, (Ci-Ce)alkanoyl, a-amino(Ci-C 4 )alkanoyl, arylactyl and a-aminoacyl, or ⁇ -aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group). It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-
  • NHC( 0)OC(CH 3 ) 2 C 6 H 4 C 6 H 5 NHBoc), as a 9-fluorenylmethoxy amide (-NHFmoc), as a 6- nitroveratryloxy amide (-NFINvoc), as a 2-trimethylsilylethyloxy amide (-NHTeoc), as a 2,2,2-trichloroethyloxy amide (-NHTroc), as an allyloxy amide (-NHAlloc), as a 2- (phenylsulfonyl)ethyloxy amide (-NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical.
  • a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.
  • -SR thioether
  • benzyl thioether a benzyl thioether
  • autophagy inducing compounds are useful in the treatment of autophagy associated diseases, such as neurodegenerative diseases caused by mismatched proteins, such as polyglutamine expansion diseases, and can be prepared so as to be useful for the treatment of diseases caused by misfolded protein aggregates and other autophagy-related diseases.
  • One aspect of the invention relates to a method of preparing diphenylbutyl bromides comprising the steps of reacting at least two equivalents of an aryl magnesium bromide with one equivalent of a ⁇ -butyrolactone to first open the lactone and form a compound containing a primary alcohol and an aryl ketone, and then react with the resultant aryl ketone, thereby forming an tertiary alcohol; dehydrating the tertiary alcohol to form an alkene; hydrogenating the alkene; and converting the primary alcohol to a halide, such as a bromide.
  • Another aspect of the invention relates to the use of a heteroaryl magenisum bromide instead of an aryl magnesium bromide.
  • Another aspect of the invention relates to the use of another carbanion, such as a lithiate.
  • a tosylate or other sulfonate leaving group may be formed.
  • One aspect the invention provides a method for inhibiting autophagy in a subject for whom inhibition of autophagy is beneficial, comprising administering to the subject a compound of the invention such that autophagy activity in the subject is altered and treatment or prevention is achieved.
  • the subject is a human.
  • treating encompasses the administration and/or application of one or more compounds described herein, to a subject, for the purpose of providing prevention of or management of, and/or remedy for a condition.
  • Treatment for the purposes of this disclosure, may, but does not have to, provide a cure; rather,
  • treatment may be in the form of management of the condition.
  • compounds described herein are used to treat unwanted proliferating cells, including cancers,
  • treatment includes partial or total destruction of the undesirable proliferating cells with minimal destructive effects on normal cells.
  • a desired mechanism of treatment of unwanted rapidly proliferating cells, including cancer cells, at the cellular level is apoptosis.
  • preventing includes either preventing or slowing the onset of a clinically evident unwanted cell proliferation altogether or preventing or slowing the onset of a preclinically evident stage of unwanted rapid cell proliferation in individuals at risk. Also intended to be encompassed by this definition is the prevention or slowing of metastasis of malignant cells or to arrest or reverse the progression of malignant cells. This includes prophylactic treatment of those at risk of developing precancers and cancers. Also encompassed by this definition is the prevention or slowing of restenosis in subjects that have undergone angioplasty or a stent procedure.
  • subject for purposes of treatment includes any human or animal subject who has been diagnosed with, has symptoms of, or is at risk of developing a disorder wherein inhibition of autophagy would be beneficial.
  • the subject is any human or animal subject.
  • a subject may be a human subject who is at risk of or is genetically predisposed to obtaining a disorder characterized by unwanted, rapid cell proliferation, such as cancer.
  • the subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to disorders characterized by unwanted, rapid cell proliferation, and so on.
  • the compounds described herein are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
  • Another aspect of the invention relates to methods for treating autophagy associated diseases caused by misfolded protein aggregates, in a subject, comprising the step of administering to a subject an autophagy inducing compound in an amount effective to treat or prevent the disease.
  • the methods and compositions of the present invention can be used to treat, for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia, oculopharyngeal muscular dystrophy, prion diseases, fatal familial insomnia, alpha- 1 antitrypsin deficiency, dentatorubral pallidoluysian atrophy, frontal temporal dementia, progressive supranuclear palsy, x-linked spinobulbar muscular atrophy, and neuronal intranuclear hyaline inclusion disease or any other diseases caused by misfolded protein aggregates described herein.
  • Another aspect of the invention relates to methods for treating autophagy associated diseases caused by protein aggregates, in a subject, comprising the step of administering to a subject an autophagy inducing compound in an amount effective to treat or prevent the disease.
  • the methods and compositions of the present invention can be used to treat, for example, diabetes.
  • Deposition of amyloid, derived from the polypeptide hormone islet amyloid polypeptide (IAPP; 'amylin') is the single most typical islet alteration in type 2 diabetes.
  • Islet amyloid is a polymerization product of a novel ⁇ -cell regulatory product.
  • amyloid may not be of importance since there is no strict correlation between the degree of islet amyloid infiltration and the disease.
  • amyloid is important in subjects where islets have been destroyed by pronounced islet amyloid deposits. Even when there is less islet amyloid the deposits are widely spread, and ⁇ -cells show ultrastructural signs of cell membrane destruction.
  • type 2 diabetes is heterogeneous and that in one major subtype aggregation of IAPP into amyloid fibrils is determining the progressive loss of ⁇ - cells.
  • development of islet amyloid may be an important event in the loss of ⁇ -cell function after islet transplantation into type 1 diabetic subjects.
  • the disease is type I diabetes. In certain embodiments, the disease is type II diabetes.
  • the methods and compositions of the present invention may also be used to treat other diseases associated with autophagy.
  • diseases may include cancer.
  • the cancer may be any cancer wherein the induction of autophagy would inhibit cell growth and division, reduce mutagenesis, remove mitochondria and other organelles damaged by reactive oxygen species or kill developing tumor cells.
  • the cancer may be cancer of the breast, liver, prostate, stomach, colon, GI tract, pancreases, skin, head, neck, throat, bladder, eye, esophagus, lung, kidney, or brain.
  • One aspect of the invention relates to a method of treating or preventing cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, enantiomer or stereoisomer thereof.
  • Chloroquine causes a dose-dependent accumulation of large autophagic vesicles and enhances alkylating therapy-induced cell death to a similar degree as knockdown of ATG5.
  • CML chronic myelogenous leukemia
  • chloroquine markedly enhanced death of a CML cell line, K562, induced by imatinib.
  • imatinib- resistant cell lines, BaF3/T315I and BaF3/E255K can be induced to die by co-treatment with imatinib and chloroquine.
  • Lymphoblastic Leukemia Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma,
  • Brain Tumor Ependymoma
  • Brain Tumor Medulloblastoma
  • Lymphocytic Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T- Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non- Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Ma
  • Thymoma Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult
  • Oropharyngeal Cancer Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer
  • the methods of the present invention may be useful to treat such types of cancer.
  • Another aspect of the invention relates to a method of treating or preventing acute pancreatitis, comprising the step of administering to a subject in need thereof a
  • Pancreatitis is an inflammation of the pancreas mediated by the release of digestive enzymes that eventually lead to the destruction of the organ itself. Pancreatitis can be a severe, life-threatening illness with many complications. In severe cases, bleeding, tissue damage to the heart, lungs and kidneys, and infection may occur. About 80,000 cases of acute pancreatitis occur annually in the United States; about 20 percent of them are severe. There is no known treatment for pancreatitis. The current approaches for managing pancreatitis involve waiting for it to resolve on its own and the treatment of heart, lungs and kidney complications if that occur.
  • Atg5-/- mice which are defective for a key autophagy gene Atg5
  • the severity of acute pancreatitis induced by cerulein is greatly reduced with a significantly decreased level of trypsinogen activation.
  • activation of autophagy may exert a detrimental effect in pancreatic acinar cells by mediating the activation of trypsinogen to trypsin.
  • Inhibition of autophagy may provide a unique opportunity for blocking trypsinogen activation in acute pancreatitis.
  • Development of an autophagy inhibitor may provide a first-in-class inhibitor for acute pancreatitis.
  • Another aspect of the invention relates to a method of treating or preventing a disease caused by an intracellular pathogen, comprising the step of administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, enantiomer or stereoisomer thereof.
  • a method of treating or preventing a disease caused by an intracellular pathogen comprising the step of administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, enantiomer or stereoisomer thereof.
  • the intracellular pathogen is selected from the group consisting of Group A streptococcus, Listeria monocytogenes, Mycobacterium tuberculosis, Vibrio cholerae, Salmonella enterica, Staphylococcus aureus, Bacillus anthracis,
  • Burkholderia pseudomallei Helicobacter pylori, Pseudomonas syringae, Toxoplasma gondeii, Sindbis virus, Vesicular stomatitis virus and Herpes simplex virus.
  • the methods of the invention further include administering to a subject a
  • an autophagy inducing compound in combination with another pharmaceutically active compound known to treat an autophagy associated disease; or a compound that may potentiate the autophagy inducing activity of the autophagy inducing compound.
  • Other pharmaceutically active compounds that may be used can be found in Harrison's Principles of Internal Medicine, Thirteenth Edition, Eds. T.R. Harrison et al. McGraw-Hill N.Y., NY; and the Physicians Desk Reference 50th Edition 1997, Oradell New Jersey, Medical Economics Co., the complete contents of which are expressly incorporated herein by reference.
  • the combination therapy contemplated by the invention includes, for example, administration of a compound of the invention, or a
  • co-administration shall mean the administration of at least two agents to a subject so as to provide the beneficial effects of the combination of both agents.
  • the agents may be administered simultaneously or sequentially over a period of time.
  • the combinations included within the invention are those combinations useful for their intended purpose.
  • the agents set forth below are illustrative for purposes and not intended to be limited.
  • the combinations, which are part of this invention can be the compounds of the present invention and at least one additional agent selected from the lists below.
  • the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
  • an autophagy inhibitor e.g., a compound of formula I
  • an anti-angiogenesis inhibitors for the treatment of cancers.
  • anti-angiogenesis inhibitors have the promise to inhibit tumor growth by suppressing the growth of blood vessels in tumors which are required for supporting tumor survival and growth.
  • the angiostatic agent endostatin and related chemicals can suppress the building of blood vessels and reduce tumor growth.
  • anti-angiogenesis drugs are now under way. In tests with patients, anti-angiogenesis therapies are able to suppress tumor growth with relatively few side effects. However, anti-angiogenesis therapy alone may not be
  • autophagy inhibitors may provide a new option to work alone or in combination with anti-angiogenesis therapy.
  • Endostatin has been shown to induce autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels (Nguyen, T.M., et al, Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels. J Cell Mol Med, 2009). As disclosed herein, it has been found that inhibition of autophagy selectively kills a subset of cancer cells under starvation condition. Therefore, it is proposed that anti-angiogenesis therapy may induce additional metabolic stress to sensitize cancer cells to autophagy inhibitors, which are not normally cytotoxic.
  • a combination of anti-angiogenesis therapy and anti-autophagy therapy may provide a new option for treatment of cancers without cytotoxicity to normal cells (Ramakrishnan, S., et al, Autophagy and angiogenesis inhibition. Autophagy, 2007. 3(5): p. 512-5).
  • Non-limiting examples of anti-angiogenesis agents with which a compound of the invention of the invention can be combined include, for example, the following:
  • bevacizumab (Avastin®), carboxyamidotriazole, TNP-470, CM101, IFN-a, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids with heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, thrombospondin, prolactin, ⁇ 3 inhibitors and linomide.
  • autophagy inhibitors can be used to treat a subject who has been identified as having a glycolysis dependent cancer by combining one or more autophagy inhibitors with one or more anti-cancer compounds which converts glycolysis dependent cancer to cells incapable of glycolysis.
  • anti-cancer compounds which convert glycolysis dependent cancer to cells incapable of glycolysis: Alkylating Agents; Nitrosoureas; Antitumor Antibiotics; Corticosteroid Hormones; Anti-estrogens; Aromatase Inhibitors; Progestins; Anti-androgens; LHRH agonists; Kinase Inhibitors; and Antibody therapies; for example, busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), mechlorethamine (nitrogen mustard), melphalan, carmustine (BCNU), lomustine (CCNU), dactinomycin, daunorubicin, doxorubicin (Adriamycin), idarubicin, mitoxantrone, prednisone, dexamethasone, tamoxifen, fulvestrant, anastrozole, letroz
  • the invention features compositions, kits, and methods for treating or preventing a disease or condition associated with diseases caused by misfolded protein aggregates or additional autophagy-related diseases by administering a compound of the invention (i.e., an autophagy inducing compound).
  • a compound of the invention i.e., an autophagy inducing compound.
  • Compounds of the present invention may be administered by any appropriate route for treatment or prevention of a disease or condition associated with misfolded protein aggregates or additional autophagy-related diseases. These may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form.
  • Administration may be topical, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, by suppositories, or oral administration.
  • Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, ear drops, or aerosols.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers may be used to control the release of the compounds.
  • Nanoparticulate formulations may be used to control the biodistribution of the compounds.
  • Other potentially useful parenteral delivery systems include ethylene -vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.
  • the compound may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry.
  • acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoro acetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like.
  • Metal complexes include zinc, iron, and the like.
  • the autophagy inducing compound has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )); ( ⁇ ) a narrow absorption window in the gastro-intestinal tract; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
  • a narrow therapeutic index e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )
  • ⁇ a narrow absorption window in the gastro-intestinal tract
  • a short biological half-life so that frequent dosing during a day is required in order to sustain
  • controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanop articles, patches, and liposomes.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas,
  • Formulations for oral use may also be provided in unit dosage form as chewable tablets, tablets, cap lets, or capsules (i.e., as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium).
  • the formulations can be administered to human subjects in therapeutically effective amounts. Typical dose ranges are from about 0.01 ⁇ g/kg to about 2 mg/kg of body weight per day.
  • the preferred dosage of drug to be administered is likely to depend on such variables as the type and extent of the disorder, the overall health status of the particular subject, the specific compound being administered, the excipients used to formulate the compound, and its route of administration. Routine experiments may be used to optimize the dose and dosing frequency for any particular compound.
  • the autophagy inducing compound is administered at a concentration in the range from about 0.001 ⁇ g/kg to greater than about 500 mg/kg.
  • the concentration may be 0.001 ⁇ g/kg, 0.01 ⁇ g/kg, 0.05 ⁇ g/kg, 0.1 ⁇ g/kg, 0.5 1.0 10.0 ⁇ , 50.0 100.0 500 1.0 mg/kg, 5.0 mg/kg,
  • the autophagy inducing compound is administered in doses that range from 0.01 ⁇ to greater than or equal to 500 ⁇ .
  • the dose may be 0.01 ⁇ , 0.02 ⁇ , 0.05 ⁇ , 0.1 ⁇ , 0.15 ⁇ , 0.2 ⁇ , 0.5 ⁇ , 0.7 ⁇ , 1.0 ⁇ , 3.0 ⁇ , 5.0 ⁇ , 7.0 ⁇ , 10.0 ⁇ , 15.0 ⁇ , 20.0 ⁇ , 25.0 ⁇ , 30.0 ⁇ , 35.0 ⁇ , 40.0 ⁇ , 45.0 ⁇ , 50.0 ⁇ , 60.0 ⁇ , 70.0 ⁇ , 80.0 ⁇ , 90.0 ⁇ , 100.0 ⁇ , 150.0 ⁇ , 200.0 ⁇ , 250.0 ⁇ , 300.0 ⁇ , 350.0 ⁇ , 400.0 ⁇ , 450.0 ⁇ , to greater than about 500.0 ⁇ or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed by the present invention.
  • the autophagy inducing compound is administered at concentrations that range from 0.10 ⁇ g/ml to 500.0 ⁇ g/ml.
  • the concentration may be 0.10 ⁇ g/ml, 0.50 ⁇ g/ml, 1 ⁇ g/ml, 2.0 ⁇ g/ml, 5.0 ⁇ g/ml, 10.0 ⁇ g/ml, 20 ⁇ g/ml, 25 ⁇ g/ml, 30 ⁇ g/ml, 35 ⁇ g/ml, 40 ⁇ g/ml, 45 ⁇ g/ml, 50 ⁇ g/ml, 60.0 ⁇ g/ml, 70.0 ⁇ g/ml, 80.0 ⁇ g/ml, 90.0 ⁇ g/ml, 100.0 ⁇ g/ml, 150.0 ⁇ g/ml, 200.0 ⁇ g/ml, 250.0 ⁇ g/ml, 300.0 ⁇ g/ml, 350.0 ⁇ g/ml, 400.0 ⁇ g/ml, 450.0
  • the present invention discloses a kit which includes a pharmaceutical composition comprising an autophagy inducing compound of the present invention (e.g. a compound of formula I) and instructions for administering the composition to a subject for the treatment or prevention of an autophagy associated disease, e.g., a disease caused by misfolded protein aggregates.
  • an autophagy inducing compound of the present invention e.g. a compound of formula I
  • the pharmaceutical composition may include one or more autophagy inducing compounds.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier.
  • Diphenylbutylpiperidines compounds such as those described below, can be prepared by S N 2 substitution of diphenylbutyl halide compounds with piperidines (as described in Janneke, W.; Hulshof, H. F.; Vischer, H.P.; Verheij, S. A.; Fratantoni, Martine, J. S.; Iwan, J. P. Bioorg. Med. Chem. Lett. 2006, 14, 7213).
  • piperidines as described in Janneke, W.; Hulshof, H. F.; Vischer, H.P.; Verheij, S. A.; Fratantoni, Martine, J. S.; Iwan, J. P. Bioorg. Med. Chem. Lett. 2006, 14, 7213.
  • synthetic routes to diphenylbutyl bromide 10 have been reported (see Janneke, W.; Hulshof, H. F.;
  • Figures 6 and 7 contain the results of incorporating various chemical moieties into the butyl linkers between the diphenyl moiety and the piperidine.
  • Autophagy inducing activity may be determined as described in International Patent Application publication number WO/2009/049242.
  • modification of the linker decreased the autophagy inducing activity, as compared to compound 1.
  • compound 31 showed the same activity as compound 30.
  • Compounds 23 and 33 which contain amide linkages, showed no autophagy activity, perhaps due to in vivo hydrolysis.
  • compounds 24-27 wherein one of the biphenyl phenyl rings is replaced with a hydrogen, showed no activity, suggestiung that the diphenyl moeity is essential.
  • Diphenylbutylpiperidines compounds such as those described herein, can be prepared by S N 2 substitution of halodiphenylbutyl compounds with piperidines (as described in Janneke, W.; Hulshof, H. F.; Vischer, H.P.; Verheij, S. A.; Fratantoni, Martine, J. S.; Iwan, J. P. Bioorg. Med. Chem. Lett. 2006, 14, 7213).
  • Figures 18 and 19 showed the biological activity of selected P-l-56 compounds.
  • compound 109 showed 2-fold increased potent activity comparable to compound 2.
  • a series of compounds with CN group have also been prepared; interestingly, some showed good results (147 vs 155, 151 vs 159, 153 vs 161) while some did not (149 vs 157, 150 vs 158, 152 vs 160).
  • compounds 149, 150, 152 and 153 showed 3 to 5-fold increased activity comparable to compound 2, while compounds 148, 151 and 154 showed no activity.
  • compounds 157, 158 and 160 showed 3 to 7-fold increased activity comparable to compound 2, while compounds 156 and 162 showed no activity. All of the above results indicate that the 4-position of piperidine ring can tolerate 6,5-fused heterocycle groups.
  • Cyclization 187 with different regents gave compounds 191, 193, 195 and 197 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Kasuya, Y.; Shigenobl, K.; Hashikami, M.; Karashima, N. Chem. Pharm. Bull. 1985, 33, 1116; and Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Hashimoto, T. Chem. Pharm. Bull. 1985, 33, 1104).

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Abstract

La présente invention concerne des composés inducteurs de l'autophagie, leurs procédés de préparation et d'utilisation, ainsi que des nécessaires en contenant.
PCT/US2011/036272 2010-05-14 2011-05-12 Inducteurs, à base de diphénylbutylpipéridine, de l'autophagie Ceased WO2011143444A2 (fr)

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CN104098479A (zh) * 2014-07-28 2014-10-15 昆明学院 含芳环的胺类化合物及其制备方法和应用
CN104098479B (zh) * 2014-07-28 2016-02-10 昆明学院 含芳环的胺类化合物及其制备方法和应用
CN105254602A (zh) * 2014-07-28 2016-01-20 昆明学院 含芳环的胺类化合物及其制备方法和应用
CN105237418A (zh) * 2014-07-28 2016-01-13 昆明学院 含芳环的胺类化合物及其制备方法和应用
WO2016119856A1 (fr) * 2015-01-29 2016-08-04 Universite De Strasbourg Molécules induisant une autophagie permettant d'augmenter la libération d'insuline
EP3359526A4 (fr) * 2015-10-05 2019-04-03 The Trustees of Columbia University in the City of New York Activateurs de flux autophagique et de phospholipase d et clairance d'agrégats de protéines comprenant tau et traitement de protéinopathies
WO2017062500A2 (fr) 2015-10-05 2017-04-13 The Trustees Of Columbia University In The City Of New York Activateurs de flux autophagique et de phospholipase d et clairance d'agrégats de protéines comprenant tau et traitement de protéinopathies
US10487091B2 (en) 2015-10-05 2019-11-26 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US10865214B2 (en) 2015-10-05 2020-12-15 The Trustees of Columbia University in they City of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11008341B2 (en) 2015-10-05 2021-05-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11230558B2 (en) 2015-10-05 2022-01-25 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11261199B2 (en) 2015-10-05 2022-03-01 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
JP2023537994A (ja) * 2020-08-11 2023-09-06 ボード オブ トラスティーズ オブ ミシガン ステイト ユニバーシティ プロテアソームエンハンサーおよびその使用
WO2023133086A1 (fr) * 2022-01-05 2023-07-13 Northwestern University Induction d'autophagie incomplète pour traitement du cancer
CN117736124A (zh) * 2023-03-21 2024-03-22 杭州天玑济世生物科技有限公司 萘胺类线粒体自噬诱导剂的固体形式、其制备方法、药物组合物和用途

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